Novel intermediate and process useful in the preparation of -(2-chlorophenyl)-methanone

ABSTRACT

The present invention relates to novel compounds, (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate, and (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone toluate, which are useful intermediates for the preparation of the compound of Formula I: 
     
       
         
         
             
             
         
       
     
     The present invention further relates to novel processes for preparing a crystalline compound, which is {2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, Form IV.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 14/937,051, filed Nov. 10, 2015, which is a continuation ofU.S. patent application Ser. No. 14/227,857, filed Mar. 27, 2014 (nowabandoned); which is a divisional application of U.S. patent applicationSer. No. 12/515,794, filed May 21, 2009 (now U.S. Pat. No. 8,772,496);which is a 35 U.S.C. §371 US national stage of PCT Patent ApplicationSerial No. PCT/US2007/086319, filed Dec. 4, 2007; which in turn claimedthe benefit of U.S. Provisional Application Ser. No. 60/870,851. Each ofthe foregoing patent applications is incorporated herein as though fullyset forth.

BACKGROUND OF THE INVENTION

The present invention relates to novel intermediates and a novel processfor the preparation of antagonists of the NK1 subtype of tachykininreceptor. Specifically, the present invention provides novelintermediates and a novel process for the preparation of{2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,Form IV.

The compound{2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,depicted below as the compound of Formula I, was first described in PCTpublished application WO2003/091226.

Because the compound of Formula I is an antagonist of the NK-1 subtypeof tachykinin receptor, it is useful for the treatment of disordersassociated with an excess of tachykinins. Such disorders includedepression, including major depressive disorder; anxiety, includinggeneralized anxiety disorder, panic disorder, obsessive compulsivedisorder, and social phobia or social anxiety disorder; schizophreniaand other psychotic disorders, including bipolar disorder;neurodegenerative disorders such as dementia, including senile dementiaof the Alzheimer's type or Alzheimer's disease; disorders of bladderfunction such as bladder detrusor hyper-reflexia and incontinence,including urge incontinence; emesis, including chemotherapy-inducednausea and acute or delayed emesis; pain or nociception; disordersassociated with blood pressure, such as hypertension; disorders of bloodflow caused by vasodilation and vasospastic diseases, such as angina,migraine, and Reynaud's disease; hot flushes; acute and chronicobstructive airway diseases such as adult respiratory distress syndrome,bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, andasthma; inflammatory diseases such as inflammatory bowel disease;gastrointestinal disorders or diseases associated with the neuronalcontrol of viscera such as ulcerative colitis, Crohn's disease,functional dyspepsia, and irritable bowel syndrome (includingconstipation-predominant, diarrhea-predominant, and mixed irritablebowel syndrome); and cutaneous diseases such as contact dermatitis,atopic dermatitis, urticaria, and other eczematoid dermatitis.

In PCT published application, WO2005/042515, novel crystalline forms ofthe compound of Formula I, identified as Form IV and Form V, areidentified. Also described in WO2005/042515 is a process for preparationof the compound of Formula I, comprising reacting(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanoneor a phosphate salt thereof with1-azidomethyl-3,5-bistrifluoromethylbenzene in the presence of asuitable base and a solvent. Use of this procedure results in severalshortcomings for synthesis on a commercial scale. For example, use ofthe solvent DMSO, with(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonephosphate, requires a complex work-up that has a propensity to emulsify.This process also requires extraction with CH₂Cl₂, the use of which isdiscouraged due to its potential as an occupational carcinogen, as wellas the use of MgSO₄ and acid-washed carbon, which can generate largevolumes of waste on a commercial scale. Conducting the reaction with(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonein isopropyl alcohol, as also described in WO2005/042515, is alsoundesirable due to the need to incorporate a free base step.Furthermore, variable levels of residual1-azidomethyl-3,5-bistrifluoromethylbenzene, a known mutagen, areobtained from use of the procedures described in WO2005/042515.

An improved process for preparing the compound of Formula I wouldcontrol the level of 1-azidomethyl-3,5-bistrifluoromethylbenzeneimpurity, and improve the yield. We have discovered that use of thenovel salt,(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate, as well as use of tert-butanol as the reaction solvent,improves reaction times and final yield, and decreases impurities in thefinal product. In addition, a novel process for the preparation of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate, in which a pre-formed enolate of 4-acetyl pyridine is added to(2-phenylsulfonyl-pyridine-3-yl)-(2-chlorophenyl)methanone, results inan overall improved yield and improved purity, and is useful on acommercial scale.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds,(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate, and(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonetoluate, which are useful intermediates for the preparation of thecompound of Formula I.

The present invention further relates to a process for preparing acrystalline compound, which is{2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,Form IV, comprising: crystallizing the product from a solvent mixture ofisopropyl acetate and heptanes.

The present invention further relates to a process for preparing acompound of Formula I comprising reacting a salt of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonewith 1-azidomethyl-3,5-bistrifluoromethylbenzene in the presence oftert-butanol.

DETAILED DESCRIPTION OF THE INVENTION

The terms and abbreviations used in the preparations and examples havetheir normal meanings unless otherwise designated. Other abbreviationsinclude the following: “h” refers to hour or hours; “HPLC” refers tohigh performance liquid chromatography; “HRMS” refers to high resolutionmass spectrometry; “i-PrOAc” refers to isopropyl acetate; “KOtBu” refersto potassium tert-butoxide; “min” refers to minute or minutes; “MS”refers to mass spectrometry; “NMR” refers to nuclear magnetic resonancespectroscopy; “ppm” refers to parts per million; “RT” refers to roomtemperature; “TLC” refers to thin layer chromatography; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to dimethylsulfoxide; “MeOH” refersto methanol; “THF” refers to tetrahydrofuran.

As used herein, the term “heptanes” refers to a solution of monovalent,saturated aliphatic chains of 7 carbon atoms. The solution may containstraight chains (n-heptane), or a combination of straight and branchedheptanes.

One of ordinary skill in the art will recognize that an alternate namefor the compound of Formula I is: Methanone,[2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-.

The following examples further illustrate the improved process forpreparing the compound,{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,Form IV.

EXAMPLES Example 1 {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone(Form IV)

Suspend(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate (204.7 g; 1.04 equiv; 445 mmoles) in t-butanol (614 mL) andtreat the slurry with potassium carbonate (124.2 g; 898.6 mmoles). Heatto 70° C. with mechanical stirring for 1 hour. Add1-azidomethyl-3,5-bistrifluoromethylbenzene (115.6 g; 1.00 equiv; 429.4mmoles) in a single portion, then heat the mixture to reflux. Acirculating bath is used to maintain a condenser temperature of 30° C.After 18 hours at reflux, HPLC reveals that the reaction is complete(<2% 1-azidomethyl-3,5-bistrifluoromethylbenzene remaining). The mixtureis cooled to 70° C., isopropanol (818 mL) is added, then the mixture isstirred at 70° C. for 1 hour. The mixture is filtered, and the wastefilter cake is rinsed with isopropanol (409 mL). The combined filtrateand washes are transferred to a reactor, and the mechanically stirredcontents are heated to 70° C. To the dark purple solution, water (1.84L) is added slowly over 35 minutes. The solution is cooled to 60° C.,then stirred for 1 hour, during which time a thin precipitate forms. Themixture is slowly cooled to RT, then the solid is filtered, washed with1:1 isopropanol/water (614 mL), subsequently washed with isopropanol(410 mL), then dried in vacuo at 45° C. to produce 200.3 g of crude{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3,]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanoneas a white solid. Crude{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone(200.3 g) and isopropyl acetate (600 mL) are charged to a 5 L 3-neckjacketed flask, then the contents heated to 75° C. After dissolution isachieved, the vessel contents are cooled to 55° C., then the solutionpolish filtered through a 5 micron filter, and the filter rinsed with avolume of isopropyl acetate (200 mL). After the polish filtrationoperation is complete, the filtrates are combined, and the vesselcontents are adjusted to 50° C. After stirring for at least 15 minutesat 50° C., 0.21 grams of{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanoneForm IV seed (d90=40 microns) is added, and the mixture stirred at 50°C. for at least 2 h. Heptanes (1.90 L) are then added over at least 2 h.After the heptanes addition is completed, the slurry is stirred for anhour at 50° C., cooled to 23° C. at a rate less then 20° C. per hour,then aged at 23° C. for an hour prior to isolation. The mixture is thenfiltered in portions through the bottom outlet valve in the reactor intoa 600 mL filter. The resulting wetcake is washed portionwise with asolution containing heptanes (420 mL) and isopropyl acetate (180 mL),which is passed directly through the 5 L crystallization vessel. Thewetcake is blown dry for 5 minutes with nitrogen, then transferred to a500 mL plastic bottle. The product is dried at 50° C. for 4 h. toproduce 190.3 g of pure {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,Form IV in 75.0% yield with 100% purity, as determined by HPLC analysis.Particle size is reduced via pin or jet mill. ¹H NMR (400 MHz, CDCl₃):5.46 (s, 2H); 7.19 (m, 5H); 7.36 (dd, 1H, J=4.9, 7.8); 7.45 (s, 2H);7.59 (m, 1H); 7.83 (s, 1H); 7.93 (dd, 1H, J=1.5, 7.8); 8.56 (dd, 1H,J=1.5, 4.9); 8.70 (d, 2H, J=5.9).

Preparation 1-A(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate

Charge powdered KOtBu (221.1 g, 1.93 moles, 1.40 eq.) to Reactor A, thencharge DMSO (2 L) at 25° C. over 10 min. The KOtBu/DMSO solution isstirred for 30 min at 23° C., then a solution of 4-acetyl pyridine (92mL, 2.07 moles, 1.50 eq) in DMSO (250 mL) is prepared in reactor B. Thecontents of reactor B are added to Reactor A over 10 minutes, then theReactor A enolate solution is stirred at 23° C. for 1 h. In a separate12-L flask (Reactor C), solid LiOH (84.26 g, 3.45 moles, 2.0 eq) ispoured into a mixture of(2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone (500.0 g, 1.34moles, 1.0 eq) and DMSO (2 L), with stirring, at 23° C. The enolatesolution in reactor A is then added to Reactor C over a period of atleast 15 minutes, and the red suspension warmed to 40° C. The reactionis stirred for 3 h, after which time HPLC analysis reveals less than 2%(2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone. Toluene (2.5L) is charged, and the reactor temperature cooled to 30° C. The mixtureis quenched by addition of glacial acetic acid (316 mL, 5.52 moles, 4.0eq), followed by 10% NaCl (2.5 L). The biphasic mixture is transferredto a 22-L bottom-outlet Morton flask, and the aqueous layer is removed.The aqueous layer is then extracted with toluene (750 mL). The combinedorganic layers are washed with 10% NaCl (750 mL), then concentrated to 4volumes and transferred to a 12-L Morton flask and rinsed with isopropylacetate (4 vol, 2 L). The opaque amber solution is warmed to 75 degreesto 75° C. over 40 min. Benzoic acid (171.1 g, 1.34 moles, 1.0 eq) isdissolved in hot isopropyl acetate (1.5 L), and charged to the crudefree base solution over at least 30 min. The crude solution containingbenzoate salt is stirred for 0.5 h at 75° C. then cooled to 23° C. Whensolids are first observed, the cooling is stopped and the mixture isaged for an hour at the temperature at which crystals are firstobserved. Alternatively, if seed crystal is available, the mixture maybe seeded with(2-chlorophenyl)[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate (2.25 g) at 75° C., followed by stirring for 0.5 h at 75° C.,then cooling to 23° C. over at least 1.5 h. The mixture is then cooledto <5° C., then filtered through paper on a 24 cm single-plate filter.The filtercake is then rinsed with cold i-PrOAc (750 mL) to producegranular crystals of bright orange-red color. The wet solid is dried at55° C. to produce 527.3 g (83% yield) with 99.9% purity.(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate. Anal. Calcd. for C₂₆H₁₉N₂ClO₄: C, 68.05; H, 4.17; N, 7.13.Found: C, 67.89; H, 4.15; N 6.05. HRMS: calcd for C₁₉H₁₃ClN₂O₂,336.0666; found 336.0673.

The synthesis of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate proceeds optimally when the potassium enolate of 4-acetylpyridine is pre-formed using KOtBu in DMSO. Pre-formation of the enolateallows the SNAR (nucleophilic aromatic substitution) reaction to beperformed between room temperature and 40° C., which minimizes theamount of degradation. Under these conditions, the SNAR is highlyregioselective, resulting in a ratio of approximately 95:5 preferentialC-acylation. In all cases, less polar solvents such as THF or toluene,or co-solvents of these solvents mixed with DMSO, results in asubstantial increase of acylation at the oxygen in the SNAR, and leadsto a lower yield of product. This is a substantial improvement over theprocedures described in WO2005/042515 for synthesis of the free base orthe phosphate salt, in which the SNAR is performed at 60-70° C.,resulting in a substantial increase in chemical impurity. Using theconditions described in WO02005/042515, when scaled to 2 kg, results inmaximum yields of 55%, with sub-optimal potency. In comparison, theimproved conditions described herein can be run reproducibly from 0.4 to2 kg scale to give yields of 77-83%, with >99% purity. In addition, thereaction can be held overnight at 40° C. with minimal degradation,whereas holding the reaction for 1 h past completion at 60-70° C.results in substantial aromatized impurity. The reaction may also beperformed using sodium tert-amylate as the base, in combination with anaprotic solvent, such as DMSO or DMF.

The title compound exists as a mixture of tautomers and geometricisomers. It is understood that each of these forms is encompassed withinthe scope of the invention.

Preparation 1-B(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonetoluate

The procedure described in Preparation 1-A is followed, with thefollowing exception. Solid toluic acid (1.0 eq) is added to the crudefree base solution at 55° C., then the solution cooled to 45° C. Thesolution is stirred for one hour at 45° C., then slowly cooled to 23° C.When solids are first observed, the cooling is stopped and the mixtureis aged for an hour at the temperature at which crystals are firstobserved. Alternatively, if seed crystal is available, the mixture maybe seeded, aged for 3 h at 45° C. , then cooled to 0° C. over 4 h. Theisolation slurry is filtered, and the wetcake washed with MeOH (3volumes). The wetcake is dried at 50° C. to provide 14.0 g (76.4%) of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonetoluate as a light red powder.

As with the benzoate salt, the toluate salt can also exist as a mixtureof tautomers and geometric isomers, each of which is encompassed withinthe scope of the invention.(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonetoluate. ¹³C NMR (125 MHz, DMSO-d6) δ 194.5, 167.8, 167.4, 155.5, 150.7(2C), 147.4, 144.0, 143.4, 142.7, 138.6, 133.0, 130.8, 130.7, 130.5,129.8(2C), 129.5(2C), 128.5, 128.0, 127.9, 119.9(2C), 118.6, 92.6, 21.5.

Preparation 1-C(2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone

A solution of 1.3 eq of diisopropylamine (based on 2-benzenesulfonylpyridine) in 5 volumes of THF in a mechanically stirred 3-necked flaskis cooled to −70 to −75° C. To this solution is added 1.05 eq ofn-butyllithium (1.6 M in hexanes) at such a rate as to maintain thetemperature below −60° C. The light yellow solution is stirred at −60 to−70° C. for 30 minutes. Once the temperature has cooled back down to −60to −65° C., 1.0 eq of 2-benzene-sulfonyl pyridine, as a solution in 3volumes of THF, is added at the fastest rate that will maintain thereaction temperature under −60° C. A yellow suspension forms during theaddition that becomes yellow-orange upon longer stirring. This mixtureis stirred for 3 hours at −60 to −75° C., and then 1.06 eq of2-chlorobenzaldehyde, as a solution in 1 volume of THF, is addeddropwise at a sufficient rate to keep the temperature under −55° C. Thesuspension gradually turns orange-red, thins out, and then becomes aclear red solution. The reaction mixture is allowed to stir at −60 to−70° C. for 1 hour, 3N aqueous HCl (7 volumes) is added over 20-30minutes, and the temperature is allowed to exotherm to 0-10° C. Thecolor largely disappears, leaving a biphasic yellow solution. Thesolution is warmed to at least 10° C., the layers are separated, and theaqueous layer is back-extracted with 10 volumes of ethyl acetate. Thecombined organic layers are washed with 10 volumes of saturated sodiumbicarbonate solution and concentrated to about 2 volumes. Ethyl acetate(10 volumes) is added, and the solution is once again concentrated to 2volumes. The thick solution is allowed to stand overnight and is takento the next step with no purification of the crude alcohol intermediate.The crude alcohol intermediate is transferred to a 3-necked flask withenough ethyl acetate to make the total solution about 10 volumes. Theyellow solution is treated with 3.2 volumes of 10% aqueous (w/w)potassium bromide, followed by 0.07 eq of2,2,6,6-Tetramethylpiperidine-N-oxide (TEMPO). The orange mixture iscooled to 0-5° C. and treated with a solution of 1.25 eq of sodiumbicarbonate in 12% w/w sodium hypochlorite (9 volumes) and 5 volumes ofwater over 30-60 minutes while allowing the temperature to exotherm to amaximum of 20° C. The mixture turns dark brown during the addition, butbecomes yellow, and a thick precipitate forms. The biphasic light yellowmixture is allowed to stir at ambient temperature for 1-3 hours, atwhich time the reaction is generally completed. The biphasic mixture iscooled to 0-5° C. and stirred for 3 hours at that temperature. The solidis filtered off, washed with 4 volumes of cold ethyl acetate, followedby 4 volumes of water, and dried in vacuo at 45° C. to constant weight.Typical yield is 80-83% with a purity of greater than 98%. ¹H NMR (600MHz, CDCl₃-d) δ ppm 7.38 (td, J=7.52, 1.28 Hz, 1 H) 7.47 (dd, J=7.80,1.30 Hz, 1 H) 7.51 (td, J=7.79, 1.60 Hz, 1 H) 7.51 (t, J=7.89 Hz, 2 H)7.50-7.54 (m, J=7.75, 4.63 Hz, 1 H) 7.60 (t, J=7.43 Hz, 1 H) 7.73 (dd,J=7.75, 1.60 Hz, 1 H) 7.81 (dd, J=7.79, 1.56 Hz, 1 H) 8.00 (dd, J=8.44,1.10 Hz, 2 H) 8.76 (dd, J=4.63, 1.61 Hz, 1 H).

Preparation 1-D 1-azidomethyl-3,5-bistrifluoromethyl-benzene

Sodium azide (74.3 g, 1.14 mol) is suspended in water (125 mL), thenDMSO (625 mL) is added. After stirring for 30 minutes, a solutionconsisting of 3,5-Bis(trifluoromethyl)benzyl chloride (255.3 g, 0.97moles) and DMSO (500 mL) is added over 30 minutes. (The3,5-Bis(trifluoromethyl)benzyl chloride is heated to 35° C. to liquefyprior to dispensing (MP=30-32° C.)). The benzyl chloride feed vessel isrinsed with DMSO (50 mL) into the sodium azide solution, the mixture isheated to 40° C., and then maintained for an hour at 40° C., then cooledto 23° C.

In Process Analysis:

A drop of the reaction mixture is dissolved in d6-DMSO and the relativeintensities of the methylene signals are integrated (NMR verified as a0.35% limit test for 3,5-Bis(trifluoromethyl)benzyl Chloride).

Work-Up:

After the mixture reaches 23° C. , it is diluted with heptanes (1500mL), then water (1000 mL) is added, and the mixture exotherms to 35° C.against a jacket setpoint of 23° C. The aqueous layer is removed (˜2200mL), then the organic layer (approximately 1700 mL) is washed with water(2×750 mL). The combined aqueous layers (˜3700 mL) are analyzed anddiscarded.

The solvent is then partially removed via vacuum distillation with ajacket set point of 85° C., pot temperature of 60-65° C. and distillatehead temperature of 50-55° C. to produce 485 g (94.5% yield) of 51 Wt %solution title compound as a clear liquid. Heptanes can be eitherfurther removed by vacuum distillation or wiped film evaporationtechnology. ¹H NMR (400 MHz, CDCl₃): 4.58 (s, 2H); 7.81 (s, 2H); 7.90(s, 1H).

Preparation 1-E 2-benzene-sulfonyl pyridine

Charge 2-chloropyridine (75 mL, 790 mmol), thiophenol (90 mL, 852 mmol),and DMF (450 mL) to a 2 L flask. Add K₂CO₃ (134.6 g, 962 mmol), thenheat to 110° C. and stir for 18 hours. Filter the mixture, then rinsethe waste cake with DMF (195 mL). The combined crude sulfide solutionand rinses are transferred to a 5-L flask, and the waste filtercake isdiscarded. Glacial acetic acid (57 mL, 995 mmol) is added to thefiltrate, then the solution is heated to 40° C., and 13 wt % NaOClsolution (850 mL, 1.7 mol) is added over 2 hours. After the reaction iscomplete, water (150 mL) is added, then the pH of the mixture adjustedto 9 with 20% (w/v) NaOH solution (250 mL). The resulting slurry iscooled to <5° C., stirred for 1.5 h, then filtered, and the cake washedwith water (3×200 mL). The product wetcake is dried in a 55° C. vacuumoven to provide 2-benzene-sulfonyl pyridine (149 g, 676 mmol) in 86%yield: ¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, J=5.5 Hz, 1H), 8.19 (d, J=7.7Hz, 1H), 8.05 (m, 2H), 7.92 (ddd, J=9.3, 7.7, 1.6 Hz, 1H), 7.60 (m, 1H),7.54 (m, 2H), 7.44 (m, 1H); IR (KBr) 788, 984, 1124, 1166, 1306, 1424,1446, 1575, 3085 cm⁻¹; MS (TOF) m/z 220.0439 (220.0427 calcd forC₁₁H₁₀NO₂S, MH); Anal. calcd for C₁₁ ₉NO₂S: C, 60.26; H, 4.14; N, 6.39;S, 14.62. Found: C, 60.40; H, 4.02; N, 6.40; S, 14.76.

As noted above, use of the improved process of the present inventionresults in an improved habit of the crystalline Form IV compound ofFormula I. The improved habit reduces surface area of the crystal,improves the filtration, and washing, and improves the efficiency ofazide mutagen rejection. These improvements are described in greaterdetail below.

In patent application WO2005/042515, the polish filtration is carriedout in 7 volumes (L/kg) of isopropanol near its boiling point (65-83°C.), a process that is difficult and hazardous to execute in commercialmanufacturing because of the high risk of crystallization on the filterand/or vessel transfer lines due to supersaturation. In the preferredcrystallization solvent, isopropyl acetate, the polish filtration isconducted in four volumes of isopropyl acetate at temperatures from 45to 55° C. This temperature range is 35 to 45° C. lower than the boilingpoint of isopropyl acetate, which provides a key safety advantage. Underthese conditions,{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanonewill remain in solution for days, and there is no danger ofcrystallization and clogging of filter and transfer lines. Controlledcrystallization is conducted by seeding with Form IV crystals at 40-45°C., followed by a ripening period of at least 2 hrs, then addition of12-15 volumes of an anti-solvent, preferably heptanes, which maximizesprocess yields.

Larger API crystals with the preferred habit (e.g., prisms and rods, asopposed to needles) provide favorable processing characteristics,including fast filtration, efficient washing and good powder flowproperties. Data from four sample filtrations, conducted in the FLT-37Hastelloy® filter-drier on a 2-3 kg scale, are provided below. The datashow an average increase in filtration rate of three-to four-fold (Fluxdata) for the preferred isopropyl acetate/heptanes system relative tothe prior isopropyl alcohol solvent system.

Isopropyl Acetate/Heptanes Filtration

Lot Number A B C D Flux (L/m² · h.) 8,858 11,106 12,930 10,807Filtration Time (min) 11 7 8 9 Wetcake thickness (mm) 130 97 125 100

Isopropyl Alcohol Filtration

Lot Number A B C D Flux (L/m² · h.) 3,424 2,133 2,712 2,002 FiltrationTime (min) 24 43 31 32 Wetcake thickness (mm) 145 140 140 138

A unimodal particle size distribution is optimally achieved with seedingwhere seed particle size consists of a d₉₀<20 microns, seed load=0.1 wt%, seed temperature=50° C., seed age time=2 h, and heptanes feed rate=2hr. In another preferred embodiment, the seed particle size consists ofa d₉₀=40 microns, seeding temperature=55° C., seed load=0.1-2%.

In the preferred embodiment, the final product is milled to a targetparticle size for optimal use in the drug product. The preferred methodsof milling include, but are not limited to, pin mill, turbo rotor, jetmill and slurry mill. Jet mill technology produces final product withd90 of approximately 10 microns.

The preferred crystallization system using isopropyl acetate/heptanes isfound to be optimal to remove methanone positional isomer impurities andazide. Spiking studies have revealed that these impurities arecompletely purged from the final product under the preferred processingconditions described herein.

The free base of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonedoes not crystallize directly from the crude reaction mixture, andconversion to a salt form for purification is essential. The benzoateand toluate salts of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone,described herein, are readily prepared from the crude free base, asdescribed above. Both the benzoate and toluate salts have an improvedmorphology relative to the phosphate salt. Both the benzoate and toluatesalts exist in a large plated morphology as compared to the needle-likemorphology of the phosphate salt. This difference in morphology resultsin a substantially improved isolation rate for the benzoate and toluatesalts. The improved morphology translates to a higher bulk density ofisolated solid (0.4-0.5 g/L) for the benzoate or toluate salts, ascompared to the phosphate salt (0.1-0.2 g/L). This results in increaseddrier capacity. In addition, both the benzoate and toluate salts arefree flowing solids, whereas the phosphate salt appears to containconsiderable static. Generally, the benzoate salt is the most preferredembodiment.

What is claimed is:
 1. A process for preparing a compound that is{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,Form IV, comprising: crystallizing the product from a solvent mixture ofisopropyl acetate and heptanes.
 2. The process of claim 1 furthercomprising reacting a salt of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonewith 1-azidomethyl-3,5-bistrifluoromethylbenzene in the presence oftert-butanol.
 3. The process of claim 2 wherein the salt of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanoneis a benzoate salt or a toluate salt.
 4. The process of claim 3 whereinthe salt of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanoneis a benzoate salt.
 5. A compound selected from the group consisting of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanonebenzoate and(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-ylvinyl)pyridin-3-yl]methanonetoluate.
 6. The compound of claim 5 which is(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-ylvinyl)pyridin-3-yl]methanonebenzoate.